The specific aims of this competitive renewal application are: (1)[unreadable] Completion of total synthesis of chlorothricolide and kijanolide. (2)[unreadable] Completion of a total synthesis of nargenicin A1, and synthesis of[unreadable] presumed nargenicin biosynthetic intermediates. (3) Stereostructure[unreadable] assignment and total synthesis of quartomicin D3, and synthesis of[unreadable] simpler quartromicin analogs. (4) Total synthesis of A835543A[unreadable] (lepicidin) via a transannular Diels-Alder reaction of an (E,E,E)-[unreadable] cyclododeca-1,7,9-triene.[unreadable] The central theme of this proposal is the development of highly[unreadable] stereoselective syntheses of biologically active natural products by[unreadable] routes involving intramolecular Diels-Alder (IMDA) reactions. Major sub-[unreadable] goals of this program are the development of strategies or methods for[unreadable] achieving high levels of stereochemical control i the IMDA reactions.[unreadable] The major focus of methodological studies that will be performed in the[unreadable] net grant period concerns use of conformational preferences of macrocylic[unreadable] systems to control the stereochemical course of transannular Diels-Alder[unreadable] reactions in the kijanolide, nargenicin, and lepicidin syntheses. As[unreadable] with previous contributions in methodology and total synthesis from this[unreadable] program, this research to be conducted in the next grant period should[unreadable] be of great assistance to organic, bioorganic and medicinal chemists[unreadable] involved with synthetic problems that fall outside the specific goals of[unreadable] this program.[unreadable] [unreadable] The targets for these investigations possess a range of interesting and[unreadable] significant biological properties. Chlorothricolide is the aglycone of[unreadable] an antibiotic with activity against gram-positive bacteria; kijanolide[unreadable] is the aglycone of kijanimicin that is active against an unusual range[unreadable] of microorganisms, including Plasmodium burgher and P. chabaudin (e.g.,[unreadable] malaria); nargenicin is an antibiotic with significant antibacterial[unreadable] activity against Staphylococcus aureus and other gram-positive bacteria;[unreadable] the quartromicins exhibit excellent antiviral against herpes simplex[unreadable] virus type 1, influenza virus type A, and human immunodeficiency virus;[unreadable] and lepicidin is a very potent insecticidal agent that is particularly[unreadable] effective against instar mosquito larvae, and thus may be important in[unreadable] the control of malaria.[unreadable] [unreadable] In addition to these specific natural product targets, we plan to[unreadable] synthesize several compounds (118 and 119a,b) that are believed to be[unreadable] late stage intermediates in the nargenicin biosynthesis, as well as[unreadable] several quartromicin analogs (157, 158). If these analogs retain the[unreadable] anti-viral activity of the parent quartromicins, this will open up a more[unreadable] easily synthesized series for systematic analogs studies.